Systems and methods for personalized radiation therapy

ABSTRACT

Disclosed herein are methods for personalized treatment of individual patient tumors. A computer software configured to integrate with a radiation therapy treatment planning system is presented. The computer software is configured to: assign a radiation sensitivity index (RSI) of a subject&#39;s tumor based at least in part on expression levels of one or more signature genes in the tumor; calculate a recommended personalized radiation dosage (RxRSI) for the subject based at least in part on a pre-determined genomic adjusted radiation dose (GARD) value and the RSI; and provide, to the radiation therapy treatment planning system, the recommended RxRSI as a radiation therapy dose for a radiation plan.

CLAIM OF PRIORITY

This application claims priority to U.S. patent application Ser. No.16/658,961 filed on Oct. 21, 2019, which claims priority to U.S.Provisional Application No. 62/747,861 filed on Oct. 19, 2018 titled“SYSTEMS AND METHODS FOR PERSONALIZED RADIATION THERAPY”, each of whichare incorporated herein by reference.

SUMMARY

Disclosed herein are systems and methods for personalized treatment ofindividual patient tumor. In one embodiment, a method of calculating apersonalized radiation therapy dosage for a subject comprises:

-   -   determining expression levels of one or more signature genes        from a subject's tumor sample;    -   applying a linear regression model to the gene expression levels        and assigning a radiation sensitivity index (RSI) to the        subject's tumor sample;    -   calculating a genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        subject; and    -   calculating a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value.

In an additional embodiment, a method of treating a subject having atumor comprises:

-   -   determining expression levels of one or more signature genes        from a subject's tumor sample;    -   applying a linear regression model to the gene expression levels        and assigning a radiation sensitivity index (RSI) to the        subject's tumor sample;    -   calculating genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        subject;    -   calculating a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value; and    -   administering the calculated personalized radiation dosage        (RxRSI) to the subject.

In a further embodiment, a system for developing a personalizedradiation therapy treatment plan for a subject having a tumor comprises:

-   -   a processor; and    -   a memory operably coupled to the processor, the memory having        computer-executable instructions stored thereon that, when        executed by the processor, cause the processor to:    -   determine a radiation sensitivity index (RSI) of the tumor from        expression levels of one or more signature genes in the tumor;    -   determine a genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        subject;    -   calculate a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value;    -   calculate the normal tissue toxicity of the personalized        radiation dosage; and    -   provide the personalized radiation therapy treatment plan for        the subject.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1D depict RxRSI, a novel system to calculate a biologicallyoptimized personalized radiation dose. (1A) shows RSI values for 1,747non-small lung cancer samples from TCC. The distribution demonstrates abimodal peak in RSI value. (1B) shows GARD values for these samplesassuming that they received 60 Gy (n=30, d=2), a standard dose used fornon-small cell lung cancer patients. The application of a uniform RTdose to a biological heterogeneous population results in a non-uniformclinical effect which GARD represents. Similar to the RSI distribution,GARD shows heterogeneity of clinical effect with a bi-modal distribution(GARD range 8.6 to 72.8). (1C) shows patients that achieved a GARD valueof 33 or above from empiric dosing in the Moffitt lung cancer clinicalcohort have superior local control to patients whose GARD value is below33. (1D) shows personalized RT dose or RxRSI as the physical doserequired to achieve a GARD value of 33. The RxRSI for each of the 60patients in the Moffitt lung cancer clinical cohort were calculated. TheRxRSI for each patient is represented by the blue line in the graph(range −15.71-95.94). The actual empiric dose received by each patientis marked by the dots.

FIGS. 2A-2D depict a Precision RxRSI model. (2A) shows that precisionRxRSI reproduces the clinical outcome observed in the Moffitt clinicalcohort. It also depicts the probability of local control after initialtreatment with patients differentiated by having a GARD score greaterthan or less than 33, respectively. This is demonstrated by the top andbottom curves. The middle curve shows the probability of local controlfor all patients receiving a random dose within the current standard ofcare range of 50-70 Gy. The KM curves for the Moffitt clinical cohortare also represented in the figure. (2B) shows in silico clinical trialcomparing predicted outcomes for simulated patients treated uniformly to60 or 74 Gy similar to RTOG 0617. The precision RxRSI model predictsuniform dose escalation to 74 Gy would result in no improvement of pEFS.(2C) shows a distribution of RxRSI for the lung TCC modeling cohort(n=1,747). 41% of patients are biologically-optimized at 60 Gy, and anadditional 16% of patients are optimized by increasing the dose to 74Gy. Over 40% of patients are undertreated at 74 Gy according to theprecision RxRSI model. (2D) shows a comparison of results from the pLCmodel and recently reported RTOG 0617 with overlapping confidenceintervals.

FIG. 3 shows that optimizing RT dose using the RxRSI-precision modelshows significant potential to improve the radiation-associated clinicaloutcome in lung cancer. The left panel shows average outcome of 0126 vs.genomically-guided 60 or 74. The right panel shows the impact of 74 Gyin a sub-group with RxRSI 62-74.

FIG. 4 shows that optimizing and personalizing RT dose with RSI/GARD. Agenomic radiation treatment plan was developed by integrating thealgorithms for RSI, GARD and RxRSI into a commercially-available RTtreatment planning system. The system integrates imaging, biological andprescription information and generates a standard plan based on empiricdosing and an alternative genomic radiation plan based on the patient'sRSI, GARD and RxRSI. The actual treatment plans used to treat theMoffitt lung cancer clinical cohort were not retrievable. However, theclinical prescription utilized, the genomic data and clinical outcomewere retrievable from the TCC database. A set of de-identified radiationtreatment plans was created for post-operative RT in lung cancer. Fivebase plans were selected that represented common treatment areas in apost-operative lung, including central lesions, right and left-sidedlesions as well as larger and smaller fields. 6 different plans werecreated for each of the five base plans to represent differentbiological conditions requiring RxRSIs within the range observed in thecohort (48 Gy, 54 Gy, 62 Gy, 74 Gy, 88 Gy, 95 Gy). The top panels showstandard of care and genomic plan for a patient receiving post-operativeRT. The bottom panels show standard dose plan was prescribed to 54 Gy.Genomic planning calculates the RxRSI in this example as 74 Gy.

FIG. 5 shows a linear model to estimate the impact of RT dose adjustmentand normal tissue dose. Using the plans generated, the mean dose wascalculated to each normal tissue target across all 30 genomic plans. Alinear model was generated by plotting dose to PTV vs mean dose to eachof the normal tissues. The resulting linear equation was utilized tocalculate an approximate mean dose to normal tissue on a per gray basis.

FIG. 6 shows RSI distribution for the Moffitt clinical cohort (n=60) andthe TCC modeling cohort (n=1,747). Both distributions are statisticallysimilar using Anderson-Darling and Kolmogorov-Smirnov tests, p<0.001.

FIG. 7 illustrates a block diagram of an illustrative data processingsystem according to an embodiment.

DETAILED DESCRIPTION

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art. Although anymethods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments disclosed, thepreferred methods, devices, and materials are now described.

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps. By contrast, the transitional phrase “consisting of” excludes anyelement, step, or ingredient not specified in the claim. Thetransitional phrase “consisting essentially of” limits the scope of aclaim to the specified materials or steps “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention. In embodiments or claims where the term comprising is used asthe transition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

The term “patient” and “subject” are interchangeable and may be taken tomean any living organism which may be treated with compounds of thepresent invention. As such, the terms “patient” and “subject” mayinclude, but are not limited to, any non-human mammal, primate or human.In some embodiments, the “patient” or “subject” is a mammal, such asmice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, or humans. In some embodiments, the patient or subjectis an adult, child or infant. In some embodiments, the patient orsubject is a human.

The term “treating” is used herein, for instance, in reference tomethods of treating a skin disorder or a systemic condition, andgenerally includes the administration of a compound or composition or atherapy regimen which reduces the frequency of, or delays the onset of,symptoms of a medical condition. This can include reversing, reducing,or arresting the symptoms, clinical signs, and underlying pathology of acondition in a manner to improve or stabilize a subject's condition.

Radiation therapy (RT) is the medical use of radiation to treatmalignant cells, such as cancer cells. This radiation can have anelectromagnetic form, such as a high-energy photon, or a particulateform, such as an electron, proton, neutron, or alpha particle. By far,the most common form of radiation used in practice today is high-energyphotons. Photon absorption in human tissue is determined by the energyof the radiation, as well as the atomic structure of the tissue inquestion. The basic unit of energy used in radiation oncology is theelectron volt (eV); 10³ eV=1 keV, 10⁶ eV=1 MeV. At therapeutic energies,the three major interactions between photons and tissue are thephotoelectric effect, Compton effect, and pair production.

Due to biological heterogeneity, radiation therapy (RT) does notuniformly work on all tissue samples, and a uniform “one-size fits all”RT dose for a given cancer-type may not be ideal. Therefore, thereremains a need for personalized radiation dose planning methods andsystems.

Disclosed herein are methods for personalized treatment of individualpatient tumors. In one embodiment, a method of calculating apersonalized radiation therapy dosage for a subject comprises:

-   -   determining expression levels of one or more signature genes        from a subject's tumor sample;    -   applying a linear regression model to the gene expression levels        and assigning a radiation sensitivity index (RSI) to the        subject's tumor sample;    -   calculating a genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        subject; and    -   calculating a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value.

In an additional embodiment, a method of treating a subject having atumor comprises:

-   -   determining expression levels of one or more signature genes        from a subject's tumor sample;    -   applying a linear regression model to the gene expression levels        and assigning a radiation sensitivity index (RSI) to the        subject's tumor sample;    -   calculating genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        patient;    -   calculating a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value; and    -   administering the calculated personalized radiation dosage        (RxRSI) to the subject.

In some embodiments, any method known in the art may be used forobtaining a tumor sample from a subject. The tumor sample may compriseat least one living cell (preferably a plurality of cells), e.g., a cellfrom a tumor (e.g., from a biopsy), a normal cell, or a cultured cell.Commonly used methods to obtain tumor cells include surgical (the use oftissue taken from the tumor after removal of all or part of the tumor)and needle biopsies. The samples should be treated in any way thatpreserves intact the gene expression levels of the living cells as muchas possible, e.g., flash freezing or chemical fixation, e.g., formalinfixation. Any method known in the art can be used to extract material,e.g., protein or nucleic acid (e.g., mRNA) from the sample. For example,mechanical or enzymatic cell disruption can be used, followed by a solidphase method (e.g., using a column) or phenol-chloroform extraction,e.g., guanidinium thiocyanate-phenol-chloroform extraction of the RNA. Anumber of kits are commercially available for use in isolating mRNA.Purification can also be used if desired.

In some embodiments, the tumor is a cancer tumor selected fromcolorectal cancer, breast cancer, ovarian cancer, pancreatic cancer,head and neck cancer, bladder cancer, liver cancer, renal cancer,melanoma, gastrointestinal cancer, prostate cancer, small cell lungcancer, non-small cell lung cancer, sarcoma, glioblastoma, T-celllymphoma, B-cell lymphoma, endometrial cancer, and cervical cancer.

In some embodiments, any method known in the art may be used todetermine the gene expression levels in a tumor sample. Gene expressionlevels can be determined in many different ways including thequantification of fluorescence of hybridized mRNA on glass slides,Northern blot analysis, real-time reverse transcription PCR (RT-PCR),microarray or other measures of gene expression abundance.

In some embodiments, the methods include determining expression levelsof signature genes in one or more cells of a tumor. In some embodiments,the methods include determining the expression levels of a plurality ofsignature genes, e.g., two, three, four, five, six, seven, eight, nine,or all ten signature genes, as follows: androgen receptor (AR); junoncogene (c-Jun); signal transducer and activator of transcription 1(STAT1); protein kinase C, beta (PKCb); V-rel reticuloendotheliosisviral oncogene homolog A (RELA or p65); c-Abl oncogene 1 (c-Abl); smallubiquitin-like modifier 1 (SUMO1); p21 activated kinase-2 (PAK2);histone deacetylase 1 (HDAC1); and interferon regulatory factor 1(IRF1).

In some embodiments, the methods include determining expression levelsof signature genes in one or more cells of a tumor, and determining aradiation sensitivity index (RSI) of the tumor based on the expressionlevels of the signature genes. To determine the RSI, the methodsdescribed herein may use a rank-based linear algorithm.

In some embodiments, determining a radiation sensitivity index of atumor comprises applying a linear regression model to the geneexpression levels, e.g., a rank-based linear regression model. In someembodiments, the expression levels of the plurality of signature genesare weighted. A linear regression model useful in the methods describedherein includes gene expression levels and coefficients, or weights, forcombining expression levels. The coefficients can be calculated using aleast-squares fit of the proposed model to a measure of cellularradiation sensitivity. The functional form of the algorithm is givenbelow, where each of the k_(i) coefficients will be determined byfitting expression levels to a particular RSI measure:RSI=k ₁*AR+k ₂ *c-jun+k ₃*STAT1+k ₄*PKC+k ₅*RelA+k ₆ *cAbl+k ₇*SUMO1+k₈*PAK2+k ₉*HDAC+k ₁₀*IRF1

Further methods and embodiments for determining radiation sensitivityindex (RSI) are described in U.S. Pat. Nos. 8,660,801; 9,846,762; and8,655,598, which are incorporated herein by reference.

As described herein, RSI provides an indication of whether radiationtherapy is likely to be effective in treating the subject's tumor. RSIhas a value approximately between 0 and 1 (Eschrich et al., Systemsbiology modeling of the radiosensitivity network: a biomarker discoveryplatform, Int. J. Radiat. Oncol. Biol. Phys. (2009)). It should beunderstood that assigning RSI according to the linear regression modelof gene expression levels described in U.S. Pat. Nos. 8,660,801;9,846,762; and 8,655,598, is provided only as an example and that otherknown techniques for assigning radiation sensitivity can optionally beused with the systems and methods described herein.

In some embodiments, the method further comprises calculating theGenomic Adjusted Radiation Dose (GARD) for each tumor sample, and isdescribed in U.S. patent application Ser. No. 15/571,617 whichincorporated herein by reference. GARD is derived using the linearquadratic (LQ) model, the individual RSI and the radiation dose andfractionation schedule for each patient as follows:

The LQ model in its simplest form is represented by: S=e−nd(α+(βd),where n is the number of fractions of radiation, d is the dose perfraction, and α and β represent the linear and quadraticradiosensitivity parameters, respectively.

Since RSI is a molecular estimate of SF2 in cell lines (survivalfraction at 2 Gy), a patient-specific a is derived by substituting RSIfor Survival (S) in the equation above, where dose (d) is 2 Gy, n=1 andβ is a constant (0.05/Gy²). GARD is calculated using the classicequation for biologic effect shown by equation E=nd(α+βd), thepatient-specific a and the radiation dose and fractionation received byeach patient. Additionally, the GARD value can be predictive of tumorrecurrence in the subject after treatment.

In some embodiments, the method comprises calculating a personalizedradiation dosage (RxRSI) for each individual tumor or subject based on apre-determined GARD value. The personalized radiation dose or RxRSI isthe physical dose required to achieve a pre-determined GARD value. TheRxRSI is calculated using the formula below:RxRSI=GARD target value/(α+βd),

where alpha is calculated based on the patient's RSI as described aboveand beta is a constant (0.05/Gy²).

In some embodiments, a pre-determined GARD value may be calculated basedon improved outcome in a particular cancer type. In other embodiments, apre-determined GARD value may be calculated based on empiric values fora cancer type.

The pre-determined GARD value may vary depending on the cancer type. Forexample, the pre-determined GARD value for a subject suffering fromnon-small cell lung cancer is 33. In some embodiments, thepre-determined GARD value for other cancers may be more or less than 33,such as any number between 2 and 150.

The empirical radiation dose for a solid epithelial tumor ranges from 60to 80 Gy, while lymphomas are treated with 20 to 40 Gy. For example,lung cancers are treated between 60 and 74 Gy, prostate cancers aregenerally treated between 37.25 to 80 Gy, and esophageal cancers aretreated between 44 to 70 Gy. It is possible that the empirical dose thatthe patients receive is lower or higher than what they need. Apersonalized radiation dose would be ideal to achieve an improvedoutcome.

In some embodiments, the personalized radiation dose that is calculatedmay be 5% less than the empirical dosing value, may be 10% less than theempirical dosing value, may be 15% less than the empirical dosing value,may be 20% less than the empirical dosing value, may be 25% less thanthe empirical dosing value, may be 30% less than the empirical dosingvalue, may be 35% less than the empirical dosing value, may be 40% lessthan the empirical dosing value, may be 50% less than the empiricaldosing value, or may be 60% less than the empirical dosing value.

In some embodiments, the personalized radiation dose that is calculatedmay be 5% more than the empirical dosing value, may be 10% more than theempirical dosing value, may be 15% more than the empirical dosing value,may be 20% more than the empirical dosing value, may be 25% more thanthe empirical dosing value, may be 30% more than the empirical dosingvalue, may be 35% more than the empirical dosing value, may be 40% morethan the empirical dosing value, may be 50% more than the empiricaldosing value, or may be 60% more than the empirical dosing value.

In some embodiments, radiation is administered in at least about 1 Gray(Gy) fraction at least once every other day to a treatment volume. Insome embodiments, radiation is administered in at least about 2 Gyfractions at least once per day to a treatment volume. In someembodiments, radiation is administered in at least about 2 Gy fractionsat least once per day to a treatment volume for five consecutive daysper week. In another embodiment, radiation is administered in 3 Gyfractions every other day, three times per week to a treatment volume.In yet another embodiment, a total of at least about 20 Gy, about 30 Gy,about 40 Gy, about 50 Gy, about 60 Gy, about 70 Gy, about 80 Gy, about90 Gy, or about 100 Gy of radiation is administered to a subject in needthereof.

The methods disclosed herein may be practiced in an adjuvant setting.“Adjuvant setting” refers to a clinical setting in which an individualhas a history of a proliferative disease, particularly cancer, andgenerally (but not necessarily) has been treated with therapy, whichincludes, but is not limited to, surgery and/or chemotherapy. However,because of a history of the proliferative disease, these individuals areconsidered at risk of developing that disease or may harbor detectableand/or microscopic disease. Treatment or administration in the “adjuvantsetting” refers to a subsequent mode of treatment.

The methods provided herein may also be practiced in a “neoadjuvantsetting,” that is, the method may be carried out before theprimary/definitive therapy. In some aspects, the individual haspreviously been treated. In other aspects, the individual has notpreviously been treated. In some aspects, the treatment is a first linetherapy.

In some embodiments, any of the methods of treatment of RT describedherein can be administered in combination with one or more additionaltherapies to the individual, such as surgery and/or chemotherapy. Insome embodiments, various classes of chemotherapeutic agents can beadministered in combination with RT. Non-limiting examples include:alkylating agents (e.g. cisplatin, carboplatin, or oxaliplatin),antimetabolites (e.g., azathioprine or mercaptopurine), anthracyclines,plant alkaloids (including, e.g. vinca alkaloids (such as, vincristine,vinblastine, vinorelbine, or vindesine) and taxanes (such as,paclitaxel, taxol, or docetaxel)), topoisomerase inhibitors (e.g.,camptothecins, irinotecan, topotecan, amsacrine, etoposide, etoposidephosphate, or teniposide), podophyllotoxin (and derivatives thereof,such as etoposide and teniposide), and other antineoplastics (e.g.,dactinomycin, doxorubicin, epirubicin, bleomycin, mechlorethamine,cyclophosphamide, chlorambucil, or ifosfamide).

In some embodiments, a radiation therapy treatment disclosed herein maybe combined with other targeted therapies, such as immunoconjugates orantibodies coupled to cytotoxic agents. Non-limiting cytotoxic agentsthat can be coupled to an antibody include a chemotherapeutic agent, adrug, a growth inhibitory agent, a toxin (e.g., an enzymatically activetoxin of bacterial, fungal, plant, or animal origin, or fragmentsthereof), or a radioactive isotope (i.e., a radioconjugate).

Also disclosed herein are systems and methods for developing apersonalized radiation therapy treatment plan for a subject having atumor. In some embodiments, the system comprises:

-   -   a processor; and    -   a memory operably coupled to the processor, the memory having        computer-executable instructions stored thereon that, when        executed by the processor, cause the processor to:    -   determine a radiation sensitivity index (RSI) of the tumor from        expression levels of one or more signature genes in the tumor;    -   determine a genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        patient;    -   calculate a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value;    -   calculate the normal tissue toxicity of the personalized        radiation dosage; and    -   provide the personalized radiation therapy treatment plan for        the subject.

In some embodiments, the system comprises a processor and a memoryoperably coupled to the processor, the memory having computer-executableinstructions stored thereon that, when executed by the processor, causethe processor to provide a personalized radiation therapy treatment planfor the subject based on one or more of the following input:

-   -   a radiation sensitivity index (RSI) of the tumor from expression        levels of one or more signature genes in the tumor;    -   a genomic adjusted radiation dose (GARD) value based on RSI,        radiation dose and fractionation schedule of the patient;    -   a personalized radiation dosage (RxRSI) for the subject based on        a pre-determined GARD value; and    -   the normal tissue toxicity of the personalized radiation dosage.

In some embodiments, the system comprises a processor and a memoryoperably coupled to the processor, the memory having computer-executableinstructions stored thereon that, when executed by the processor, causethe processor to:

-   -   calculate a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value;    -   calculate the normal tissue toxicity of the personalized        radiation dosage; and    -   provide the personalized radiation therapy treatment plan for        the subject.

In some embodiments, the system comprises a processor and a memoryoperably coupled to the processor, the memory having computer-executableinstructions stored thereon that, when executed by the processor, causethe processor to provide the personalized radiation therapy treatmentplan for the subject based on:

-   -   personalized radiation dosage (RxRSI) for the subject; and    -   the normal tissue toxicity of the personalized radiation dosage.

In some embodiments, the method includes integrating the prescribed RTdosage into a commercially available radiation treatment planning systemthat generates personalized treatment plan based on the patient's RSI,GARD and RxRSI values. The methods disclosed herein can be implementedin digital electronic circuitry, or in computer software, firmware, orhardware, or in combinations of them.

Accordingly, as discussed herein, various embodiments may includenon-transitory computer-readable media for analyzing health information.In particular, some embodiments may have a health/diagnosis analysissystem configured to analyze, examine, search, investigate, consider,evaluate, and/or otherwise process health information and to generatevarious medical assessments based on the health information.Non-limiting examples of medical assessments include medical diagnoses,medical orders, and/or risk assessments. Health information, as usedherein, may include any type of information associated with the healthor physical characteristics of a patient, including, but not limited to,name, address, age, gender, demographic information, weight, height,medications, surgeries and other medical procedures (e.g., diagnostictests, diagnostic imaging tests, or the like), occupation(s), past andcurrent medical conditions, family history, patient description ofhealth condition, healthcare professional description of healthcondition, and/or symptoms.

In some embodiments, the analysis process may involve accessing healthinformation associated with a patient and providing a medical assessmentbased on various analyses of the health information. In someembodiments, the health information analysis system may receive inputfrom a healthcare provider concerning the accuracy, completeness,correctness, or other measure of a medical assessment for use indetermining future medical assessments.

The systems and devices described herein provide multiple technologicaladvantages on current processes and techniques. One non-limitingtechnological advantage is that the health information analysis systemmay provide medical assessments to healthcare professionals based on apatient's full medical history, including across healthcare providersand information platforms. Such analyses are generally not possibleusing conventional processes and technology because, for instance, theywould require a great deal of time to be effective and practical whenproviding healthcare to patients.

Another non-limiting technological advantage may be that the healthinformation analysis system is capable of dynamically adapting itsanalysis processes based on healthcare professional feedback, updatedinformation, or the like. A further non-limiting technological advantageis that the health information analysis system may present timely anddynamically updated information to medical professionals in a formatthat is readily comprehensible to provide a timely analysis, includingin real-time or substantially real-time. The presentation of healthinformation according to some embodiments allows medical professionalsto provide more efficient and effective healthcare to patients comparedwith conventional techniques and processes that are generallypaper-based or use limited graphical user interfaces (GUI) that are notcapable of providing a comprehensive and meaningful picture of apatient's health information.

In some embodiments, the information, or data, acquired by the systemmay generally include all information collected or generated prior tothe medical procedure. Thus, for example, information about the patientmay be acquired from a patient intake form or electronic medical record(EMR). Examples of patient information that may be collected include,without limitation, patient demographics, diagnoses, medical histories,progress notes, vital signs, medical history information, allergies, andlab results. The data may also include images related to the patient'sarea of interest. It should be understood, that the images may becaptured using any known or future medical imaging device, for example,Magnetic Resonance Imaging (MRI), Computed Tomography (CT), X-ray,ultrasound, or any other modality known in the art. The data may alsocomprise quality of life data captured from the patient. For example, inone embodiment, a patient may use a software application (“app”) toanswer one or more questionnaires regarding their current quality oflife. In a further embodiment, the health information may includedemographic, anthropometric, cultural, or other specific traits about apatient that can coincide with activity levels and specific patientactivities to customize the surgical plan to the patient. For example,certain cultures or demographics may be more likely to perform arepetitive physical task or be exposed to a particular set ofenvironmental factors.

In a further embodiment, the computer system may refine or improve thediagnosis by adjusting weighted factors and/or modifying one or moredetermination factors based on outcome data. For example, an embodimentmay utilize, a closed loop algorithm to perform statistical and machinelearning modeling. In certain implementations, the outcome data mayinclude overall survival information, progression-free survivalinformation, response rate to a specific drug, and/or other similaroutcome data.

For example, a procedure for refining weights can involve testing avariety of statistical and machine learning modeling techniques andselecting the one that performs best. For a given set of medicalprocedures, multiple models may be trained to predict the outcomes. Thebest model can be selected, or a combination and/or averaging of thebest models may be newly generated. In certain implementations, rulescan be in place to determine what alterations are made to the system.

Accordingly, the algorithm/system as described herein may includemachine learning and/or other similar statistical-based modelingtechniques. For example, the algorithm used may depend on an expectedoutcome. For example, a processing device can be configured to use afirst process or algorithm to calculate refinements to a deriveddiagnosis based upon a first set of outcome data while also using asecond or different algorithm to calculate refinements. Differentmethods and algorithms may be used to calculate the refined weights inconcert or substantially simultaneously. The output of each of thedifferent methods and algorithms can then be compared/further analyzedto determine which output is highest rated, or the output of each methodand algorithm can be combined into a combinational metric.

In some embodiments, the personalized radiation dosage (RxRSI) may becalculated using a computer program product. The computer programproduct may include a computer readable storage medium (or media) havingcomputer readable program instructions thereon for causing a processorto carry out aspects of the present invention.

The computer readable storage medium can be a non-transitory tangibledevice that can retain and store instructions for use by an instructionexecution device (e.g., one or more processors). The computer readablestorage medium may be, for example, but is not limited to, anelectronic, magnetic, optical, electromagnetic, semiconductor storagedevice, or any suitable combination of the foregoing. A non-exhaustivelist of more specific examples of the computer readable storage mediumincludes the following: a portable computer diskette, a head disk,random access memory (RAM), read-only memory (ROM), erasableprogrammable read-only memory (EPROM or Flash memory), static randomaccess memory (SRAM), a compact disc read-only memory (CD-ROM), adigital versatile disk (DVD), a memory stick, a floppy disk, amechanically encoded device such as punch-card(s) or raised structuresin a groove having instructions recorded thereon, and/or any suitablecombination of the foregoing.

A computer readable storage medium, as used herein, is not to beconstrued as being transitory signals per se, such as radio waves orother freely propagating electromagnetic waves, electromagnetic wavespropagating through a waveguide or other transmission media (e.g., lightpulses passing through a fiber-optic cable), or electrical signalstransmitted through a wire.

Computer readable program instructions described herein may bedownloaded to respective computing/processing devices from a computerreadable storage medium or to an external computer or external storagedevice via a network, for example, the Internet, a local area network(LAN), a wide area network (WAN), and/or a wireless network. The networkmay comprise conductive transmission cables (e.g., copper cables),optical transmission fibers, wireless transmission, routers, firewalls,switches, gateway computers, and/or edge servers. A network adapter cardor network interface in each computing/processing device receivescomputer readable program instructions from the network and forwards thecomputer readable program instructions for storage in a computerreadable storage medium within the respective computing/processingdevice.

The processor can process instructions for execution within thecomputing device, including instructions stored in the memory. Theprocessor can also include separate analog and digital processors. Theprocessor can provide, for example, coordination of the other componentsof the device, such as the user interface, applications, and wirelesscommunication.

The processor may communicate with a user through a control interfaceand/or a display interface coupled to a display. The display can be, forexample, a TFT LCD display, an OLED display, or other appropriatedisplay technology. The display interface can comprise appropriatecircuitry for driving the display to present graphical and otherinformation to a user. The control interface can receive commands from auser and convert them for submission to the processor. In addition, anexternal interface can be in communication with processor, so as toenable near area communication of device with other devices.

In some embodiments, the system includes computer software thatintegrates information for each individual patient including imaging,genomic and clinical data (i.e. clinical prescription). The systemgenerates a conventional standard of care (SoC) treatment plan as wellas a personalized treatment plan that incorporates the individualpatient RSI, GARD, RxRSI, and normal tissue toxicity. The physician canthen evaluate both plans and choose which one to use for the patientbased on standard dose-volume histogram (DVH) metrics of normal tissueand tumor coverage.

In some embodiments, a computer-implemented method for minimizing therisk of radiation therapy is provided. The method comprises:

-   -   obtaining a radiation sensitivity index (RSI) of a subject's        tumor from expression levels of one or more signature genes in        the tumor;    -   determining a genomic adjusted radiation dose (GARD) value based        on RSI, radiation dose and fractionation schedule of the        subject;    -   calculating a personalized radiation dosage (RxRSI) for the        subject based on a pre-determined GARD value;    -   calculating normal tissue toxicity of the personalized radiation        dosage; and    -   providing a personalized radiation therapy treatment plan for        the subject.

FIG. 7 illustrates a block diagram of an illustrative data processingsystem 700 in which aspects of the illustrative embodiments areimplemented. The data processing system 700 is an example of a computer,such as a server or client, in which computer usable code orinstructions implementing the process for illustrative embodiments ofthe present invention are located. In some embodiments, the dataprocessing system 700 may be a server computing device. For example,data processing system 700 can be implemented in a server or anothersimilar computing device operably connected to a surgical system. Thedata processing system 700 can be configured to, for example, transmitand receive information related to a patient and/or a related surgicalplan with the surgical system.

In the depicted example, data processing system 700 can employ a hubarchitecture including a north bridge and memory controller hub (NB/MCH)701 and south bridge and input/output (I/O) controller hub (SB/ICH) 702.Processing unit 703, main memory 704, and graphics processor 705 can beconnected to the NB/MCH 701. Graphics processor 705 can be connected tothe NB/MCH 701 through, for example, an accelerated graphics port (AGP).

In the depicted example, a network adapter 706 connects to the SB/ICH702. An audio adapter 707, keyboard and mouse adapter 708, modem 709,read only memory (ROM) 710, hard disk drive (HDD) 711, optical drive(e.g., CD or DVD) 712, universal serial bus (USB) ports and othercommunication ports 713, and PCI/PCIe devices 714 may connect to theSB/ICH 702 through bus system 716. PCI/PCIe devices 714 may includeEthernet adapters, add-in cards, and PC cards for notebook computers.ROM 710 may be, for example, a flash basic input/output system (BIOS).The HDD 711 and optical drive 712 can use an integrated driveelectronics (IDE) or serial advanced technology attachment (SATA)interface. A super I/O (SIO) device 715 can be connected to the SB/ICH702.

An operating system can run on the processing unit 703. The operatingsystem can coordinate and provide control of various components withinthe data processing system 700. As a client, the operating system can bea commercially available operating system. An object-orientedprogramming system, such as the Java™ programming system, may run inconjunction with the operating system and provide calls to the operatingsystem from the object-oriented programs or applications executing onthe data processing system 700. As a server, the data processing system700 can be an IBM® eServer™ System® running the Advanced InteractiveExecutive operating system or the Linux operating system. The dataprocessing system 700 can be a symmetric multiprocessor (SMP) systemthat can include a plurality of processors in the processing unit 703.Alternatively, a single processor system may be employed.

Instructions for the operating system, the object-oriented programmingsystem, and applications or programs are located on storage devices,such as the HDD 711, and are loaded into the main memory 704 forexecution by the processing unit 703. The processes for embodimentsdescribed herein can be performed by the processing unit 703 usingcomputer usable program code, which can be located in a memory such as,for example, main memory 704, ROM 710, or in one or more peripheraldevices.

A bus system 716 can be comprised of one or more busses. The bus system716 can be implemented using any type of communication fabric orarchitecture that can provide for a transfer of data between differentcomponents or devices attached to the fabric or architecture. Acommunication unit such as the modem 709 or the network adapter 706 caninclude one or more devices that can be used to transmit and receivedata.

Those of ordinary skill in the art will appreciate that the hardwaredepicted in FIG. 7 may vary depending on the implementation. Otherinternal hardware or peripheral devices, such as flash memory,equivalent non-volatile memory, or optical disk drives may be used inaddition to or in place of the hardware depicted. Moreover, the dataprocessing system 700 can take the form of any of a number of differentdata processing systems, including but not limited to, client computingdevices, server computing devices, tablet computers, laptop computers,telephone or other communication devices, personal digital assistants,and the like. Essentially, data processing system 700 can be any knownor later developed data processing system without architecturallimitation.

EXAMPLES Example 1: Personalizing Radiotherapy Prescription Dose UsingGenomic Markers of Radiosensitivity

The empiric basis of radiation therapy (RT), the most commonly utilizedtherapeutic agent in clinical oncology, has gone unmodified for over 70years. RT is prescribed based on a uniform, one-size fits all approach,delivering small daily doses of RT over several weeks (i.e.fractionation). This fractionation approach is based on studiesperformed in rams and rabbits by Regaud, Schinz and Slotopolsky over 100years ago. And the standard total doses for control of sub-clinical,microscopic and macroscopic disease (50, 60 and 70 Gy) were establishedin the 1960s based on tumor control probability models for head and neckcancer patients.

The linear quadratic (LQ) model has been a stalwart in the field thathas informed RT dose and fractionation since originally proposed byCatcheside and Lea in the 1940s. The LQ proposes that radiation responseis a two parameter function of dose delivered (one parameter, alpha, islinear in dose, and the other, beta, is quadratic). Of note, it has beenutilized to calculate equivalent dose and fractionation regimens thathave been shown to be safe and effective in clinical trials. However, afundamental limitation of the LQ model is that it assumes that tumorbiology is homogenous and that all individuals in a population have asimilar opportunity to benefit from RT, with differences in responsebeing related to probabilistic events. Thus, the LQ model predicted thatuniform RT dose escalation would result in significant clinical gainsacross multiple disease sites. Unfortunately, multiple prospective Phase3 randomized trials have recently disproven this prediction.

The development of “omic” technologies has revealed that cancer is themost heterogeneous and complex disease that affects humans. The era ofprecision medicine is focused on the identification of parameters thatdrive biological heterogeneity. Rather than a single disease with auniform treatment, the complexity and diversity of cancer requires manytreatment options that are matched and optimized based on the patient'sindividual tumor biology.

Although RT remains a critical curative agent for cancer, it has yet toadapt a biological basis in the clinic. It was previously proposed thatthe gene expression-based radiosensitivity index (RSI), a surrogate forintrinsic cellular radiosensitivity, and the genomic-adjusted radiationdose (GARD), an individualized quantitative metric of the clinicaleffect of RT, could serve as the first approach to biology-based RT.Both RSI and GARD have been validated in multiple clinical cohorts anddisease sites as a predictor of clinical outcome in patients treatedwith RT. Importantly, the Lancet Oncology commission identified GARD asa research priority in the field of radiation oncology. In addition, arecent independent study from Lund University provides corroborativeevidence that RSI is predictive of RT benefit in breast cancer; apredictive biomarker.

It is hypothesized that, given the known heterogeneity of cancer, thecurrent empiric basis for clinical dose and fractionation is asub-optimal strategy to determine RT dose for a given individualpatient. Indeed, assuming that the same dose of RT is optimal for everypatient is inconsistent with the biologic principles of precisionmedicine because, theoretically, a single dose may under treat or overtreat all patients. In this disclosure, the RSI/GARD model is utilizedto calculate a personalized RT prescription that is informed by eachindividual patient's biology within a cohort of lung cancer patientstreated with standard empiric RT dose at Moffitt Cancer Center. Thepersonalized RT prescription which is termed as RxRSI represents theprescription dose needed for each patient to achieve a GARD valueassociated with optimal local control. With this information in hand, itis able to quantify for each patient, the likely under or over-dosingcompared to predicted optimal prescription dose (RxRSI).

To quantify the penalties of over- and under-dosing, a precision RTmodel was developed which estimates local control based on whether anoptimal RT dose is delivered and then penalizes that outcome based onexposure to excess normal tissue complication risk (penalized localcontrol, pLC). Critically, the precision RT model is validated bydemonstrating that it correctly predicts the lack of local controlbenefit derived from uniform dose escalation in lung cancer demonstratedin RTOG 0617. Finally, the precision RT model estimates thatpersonalized prescription RT dose may improve the local control in lungcancer by an absolute 6.3% when compared to standard empiric RT dose.Further, it is shown within current standard of care dosing howradiation dose optimization can be achieved through biologicallyselected dose-escalation, enabling personalized medicine to enterradiation oncology clinics today.

Materials and Methods

Lung Cancer Modeling Cohort—This cohort was extracted from Total CancerCare (TCC), a prospective IRB-approved data and tissue collectionprotocol active at Moffitt and 18 other institutions since 2006. Tumorsfrom patients enrolled in the TCC protocol were arrayed on AffymetrixHu-RSTA-2a520709 (Affymetrix, Santa Clara, CA), which containsapproximately 60,000 probe sets representing 25,000 genes. Chips werenormalized using iterative rank-order normalization (IRON).Batch-effects were reduced using partial-least squares (PLS). Thenormalized, de-batched expression values for 1,747 NSCNC (NSCLC) samplesand the ten RSI-genes were extracted from the TCC database.

Lung Cancer Clinical Cohort—This cohort has been previously described.It includes a total of 60 patients with Stage 3 NSCLC treated at Moffittwith post-operative RT (dose range 45-70 Gy). All patients in the cohortwere consented for the TCC protocol and had genomic data available. Themicroarray data was normalized using the robust multiple-array average(RMA). The clinical endpoint was local control. The median follow up(based on the reverse Kaplan-Meier method) in censored patients freefrom local failure was 59.5 months (95% CI:38.0-68.5 months).

Radiosensitivity Index (RSI)—RSI scores for the TCC modeling cohort andlung cancer clinical cohort dataset were previously generated. RSI waspreviously trained in 48 cancer cell lines to predict cellularradiosensitivity as determined by survival fraction at 2 Gy (SF2). Eachof ten genes in the algorithm is ranked based on gene expression(highest expressed gene is ranked at 10 and lowest at 1), and RSI iscalculated using the pre-determined equation:RSI=−0.0098009*AR+0.0128283*cJun+0.0254552*STAT1−0.0017589*PKC−0.0038171*RelA+0.1070213*cABL−0.0002509*SUMO1−0.0092431*PAK2−0.0204469*HDAC1−0.0441683*IRF1.

Genomic Adjusted Radiation Dose (GARD)—GARD has been previouslydescribed. Briefly, it is derived using the LQ model, the individual RSIand the radiation dose/fractionation schedule for each patient. First, apatient-specific a is derived by substituting RSI for Survival (S) inthe LQ equation below where dose (d) is 2 Gy, n=1 and τ3 is a constant(0.05/Gy²):s=e ^(−nd(α+βd)).

GARD is calculated using the classic equation for biologic effect,GARD=nd (α+βd), and using the patient-specific a is calculated as statedabove, and the number of fractions (n) and dose per fraction (d)received by each patient. A GARD cut-point of 33 was previouslyidentified and published for the lung clinical cohort.

Biologically-Optimized Personalized RT dose (RxRSI)—RxRSI is thephysical dose required to achieve a previously identified GARD threshold(GARD≥33). RxRSI is calculated using the following formula:RxRSI=33/(α+βd)

-   -   where alpha is calculated based on the patient's RSI as        described above and beta is a constant (0.05/Gy²).

When comparing RxRSI to the empiric dose received by patients in thelung cancer clinical cohort, the RxRSI and empiric dose were defined asmatched if they were within 10% of each other. As GARD was developedbased on standard fractionation, it was assumed that RxRSI is deliveredin a similar manner (i.e. dose per fraction is ˜2 Gy).

Genomic Radiation Treatment Planning—To develop a treatment plan tobiologically optimize RT for individual patients, the algorithms andequations that define RSI, GARD, and RxRSI were integrated intoradiation treatment planning software. The software integratesinformation for each individual patient including imaging, genomic andclinical data (i.e. clinical prescription). The system generates aconventional standard of care (SoC) treatment plan as well as a genomictreatment plan that incorporates the individual patient RSI, GARD andRxRSI (FIG. 4 ).

To quantify the potential clinical impact of genomic radiation treatmentplanning, and to represent the diversity of plans observed in clinicalpractice, plans with both right and left-sided large targets, centraltargets and one with a small peripheral target were selected. Sixdifferent biological conditions requiring six different RxRSIs (48 Gy,54 Gy, 62 Gy, 74 Gy, 88 Gy, 95 Gy) were assumed and a total of 30radiation plans using the Eclipse treatment planning system (VarianMedical Systems, Inc., Palo Alton, CA) and standard dosimetricapproaches were generated. Dosimetric parameters for normal tissueincluding mean heart dose, mean esophagus dose, and mean right and leftlung dose were calculated for all genomic plans (Tables 2-5). Ingeneral, the esophagus (V76) became the main dose limiting structure,particularly for plans above 74 Gy. The resulting data was utilized togenerate a linear model to estimate the impact of dose personalizationon normal tissue (FIG. 5 ).

Linear Model for Normal Tissue Estimates—The mean dose to each normaltissue target (heart, left lung, right lung and esophagus) wascalculated across the 30 genomic plans developed. Mean normal tissuedose was plotted against PTV prescription dose to obtain a Pearson'scorrelation coefficient for mean heart, left lung, right lung, andesophageal dose (R²: 0.98, 0.99, 0.97, 0.99, respectively). These linearequations were then used to calculate an approximate mean dose to normaltissue on a per gray basis for modeling studies.

Normal Tissue Toxicity—Calculations for relative risk for a given dosereceived or dose adjustment was accomplished using different methods foreach tissue site, depending on the available data and recommendations inthe literature. When possible, data on the rate of complication per dosereceived or a quantitative NTCP model which has the benefit offlexibility in choosing dosing parameters was used. Forgeneralizability, specific dose-toxicity endpoints were not referenced.

In the QUANTEC review of lung complications, the primary endpoint isradiation pneumonitis. The reviewers conducted a meta-analysis ofapplicable studies and performed logistic regression on rates ofradiation pneumonitis versus mean lung dose as follows,

$p = {\frac{\exp\left( {b_{0} + {b_{1} \cdot {MLD}}} \right)}{1 + {\exp\left( {b_{0} + {b_{1} \cdot {MLD}}} \right)}}.}$

Parameters for b0 and b1 were calculated for a model in the above form.

The QUANTEC reported recommendations for toxicity endpoints for theesophagus were inconclusive due to the volume-dependent effect of theavailable data. Two of the studies, both published in 2005, providedquantitative models in the form of the Lyman-Kutcher-Burman equation,with parameters m and TD₅₀ that were within bounds of the confidenceintervals,

${NTCP} = {\frac{1}{\sqrt{2\pi}}{\int\limits_{- \infty}^{t}{e^{{- x^{2}}/2}d{x.}}}}$

Here

${t = \frac{{EUD} - {TD_{50}}}{m \times TD_{50}}},$

Cardiac complications due to radiation were modeled as a fixed rate of7.4% increased risk per 1 Gy dose received by the heart. The endpointincluded coronary events as defined by myocardial infarction, coronaryrevascularization, or death from ischemic heart disease.

Precision RxRSI Model—The clinical cohort was divided into two groupsbased on the previously identified and published cut-point for GARD inthe lung clinical cohort (GARD≥33 vs. GARD<33). Kaplan-Meier curves werefit for each group, as well as Weibull survival-type so that continuoussurvival and hazard functions could be applied more generally in furtheranalysis. Next, outcomes under a random radiotherapy dosing regimen wereestimated, under which each patient would receive a randomly selectedradiotherapy dose between 50 and 70 Gy. This dose was then compared tothe patient's individual RxRSI in order to determine probability oflocal control. The survival function for this dosing strategy wasconstructed as a linear combination of the initial two curves, withcoefficients weighted by the fractional number of patients in thatgroup. These survival curves are shown in FIG. 2A.

Validation of the precision RxRSI precision model: In silico modellingof RTOG 0617—To validate the precision RxRSI model, the results of therecently reported trial of dose escalation (60 Gy vs 74 Gy) in NSCLCwere modeled. To understand the combined contributions of tumor andexcess normal tissue effects on outcomes, penalized local control (pLC)was calculated, which includes local recurrence and events related toRT-related toxicity, but does not account for death due to diseaseprogression or other causes. To calculate this curve, 1000 iterations ofthe following algorithm were completed: from an empiric distribution of1747 NSCLC patients with measured RSI (from the Moffitt TCC cohort),which was statistically indistinguishable from the smaller 60 patientcohort reported above (p<<0.001 using Anderson-Darling andKolmogorov-Smirnov tests, FIG. 6 ), at random, 207 patients for a 74 Gyarm, and 217 patients for a 60 Gy arm were selected. RxRSI was thencalculated for each patient and this was compared to the dose received,and the patient was assigned to the appropriate GARD group for LC. Thepenalized local control curve was then modelled as S(t)=C₁S₁(t)+C₂S₂(t),where C₁=fraction of patients with GARD≥33 and C₂=fraction of patientswith GARD<33. Finally the survival curve for the 74 Gy group wasadjusted for the predicted hazard ratios in order to compare pLC for thetwo groups:pLC(t)=[S _(74Gy)(t)] ^(HR) ^(C) ^(·HR) ^(E) ^(·HR) ^(P)

-   -   where HR _(C), HR _(E), HR _(P) are the risks for each adverse        outcome due to the increased dose from 60 to 74 Gy (cardiac,        esophagitis, pneumonitis, respectively).

Statistical Methods—Kaplan-Meier curves were generated to compare localcontrol of patients that achieved a GARD of 33 or above from empiricaldosing with that of patients whose GARD was below 33. A log rank testwas used to compare the local control between GARD groups, with thelevel of significance set at 0.05 level.

Results

An Approach to Personalize RT Prescription Dose Based on IndividualTumor Biology

FIG. 1 shows a feasible clinical approach to personalize RT prescriptiondose based on biological heterogeneity. First, the significantbiological heterogeneity that the gene expression-based radiosensitivityindex estimates in lung cancer patients from the TCC cohort is shown inFIG. 1A. As shown, there is a bimodal distribution of RSI scores acrossthis population, suggesting that a uniform, one-size fits all approachto RT dose is sub-optimal for the majority of patients. Next, thedistribution of the genomic adjusted radiation dose (GARD) that resultsfrom the clinical application of uniform RT dose (60 Gy) to the TCCpopulation is shown in FIG. 1B. As expected, a uniform one-size fits allapproach to RT prescription results in large differences in RT clinicaleffect between individuals (GARD range 8.6 to 72.8). As previouslydemonstrated, patients in the Moffitt lung cancer clinical cohort (n=60)who achieve a GARD>33 when empirically treated have an improved localcontrol (FIG. 1C, 5-year LC, 78% vs. 48%, p=0.04). Finally, thepersonalized RT dose or RxRSI as the physical dose required to achieve aGARD value of 33 is defined. In FIG. 1D, the calculated RxRSI for therange of RSI values represented in the cohort (blue line) compared withthe actual dose received by each patient in the cohort is shown. It isproposed that patients that achieve a GARD of 33 are biologicallyoptimized in regards to tumor dose (blue region).

Current Empiric RT Prescription Dose does not Optimize Radiotherapy Doseat an Individual Level

Next, RxRSI was generated for every patient in the Moffitt clinicalcohort, which is summarized in Table 1 (RxRSI range 15.71-95.94). Theclinical cohort could be divided in four groups. Group 1 patients(15/60, Table 2) were those where the prescribed empiric dose and thecalculated RxRSI were within 10% of one another, which is considered asoptimized. Group 2, which represented 50% of the patients (30/60),received a lower dose by more than 10% than the estimated RxRSI,suggesting that these patients received less than an optimal dose(Tables 3 and 4) and could benefit from personalized dose escalation.Group 2 could be sub-divided into subgroup 2a and 2b based on whethertheir estimated RxRSI was within the previously defined standard of caredose range (50-70 Gy as defined by NCCN for post-operative RT for NSCLcancer). For Group 2a, (15/60), the estimated RxRSI was within thestandard of care for post-operative lung RT (50-70 Gy) as defined byNCCN (Table 3). Thus, these patients could have received their targetRxRSI dose without varying the prescribed RT dose outside the standardof care range. For patients in Group 2b, the RxRSI was above the rangeconsidered standard of care (RxRSI>70 Gy, Table 4), suggesting thatmoderate personalized dose escalation would not allow for optimizationof their radiation related outcome.

TABLE 1 Generating RxRSI: Biological Optimization of IndividualTreatment Plans Using Genomic Radiation Therapy Planning Mean Mean MeanMean Mean dose diff Group dose RSI GARD RxRSI (dose- RxRSI) Group 1 58.40.3 33 58.5 −0.5 (n = 15) Group 2A 50.67 0.33 27.74 60.35 −9.68 (n = 15)Group 2B 54.43 0.46 20.95 86.68 −32.25 (n = 15) Group 3 60.19 0.20 53.5250.92 9.27 (n = 15)

TABLE 2 Group 1 sub-cohort. In these patients, the dose delivered andthe calculated R × RSI matched. Δ number Mean Mean treatment Mean LeftRight Mean weeks Actual Esophageal Lung Lung Heart (rounded vs Δ Δ Δ Δup to Patient Actual R × RSI @ @ @ @ whole ID dose RSI GARD R × RSI DoseΔ R × RSI R × RSI R × RSI R × RSI fraction) 46 54 0.26 36.378 48.986−5.014 −1.263 −0.633 −0.551 −0.355 −1 47 60 0.31 35.126 56.369 −3.631−0.914 −0.459 −0.399 −0.257 −0.8 48 60 0.31 35.126 56.369 −3.631 −0.914−0.459 −0.399 −0.257 −0.2 49 63 0.33 34.885 59.596 −3.404 −0.857 −0.43−0.374 −0.241 −1 50 61.2 0.334 33.522 60.246 −0.954 0.24 −0.12 −0.105−0.068 0.6 51 50 0.262 33.453 49.323 −0.677 −0.171 −0.086 −0.074 −0.0480 52 54 0.292 33.192 53.688 −0.312 −0.079 −0.039 −0.034 −0.022 −0.6 5360 0.332 33.088 59.841 −0.159 −0.04 −0.02 −0.018 −0.011 0 54 61.2 0.34332.711 61.74 0.54 0.136 0.068 0.059 0.038 −0.6 55 55.8 0.312 32.46456.721 0.921 0.232 0.116 0.101 0.065 −0.4 56 61.2 0.357 31.538 64.0382.838 0.715 0.358 0.312 0.201 −0.2 57 60 0.35 31.493 62.87 2.87 0.7230.363 0.315 0.204 0.4 58 61.2 0.358 31.406 64.306 3.106 0.782 0.3920.341 0.22 −0.2 59 60 0.357 30.884 64.111 4.111 1.035 0.519 0.452 0.2910.6 60 54 0.328 30.107 59.189 5.189 1.307 0.655 0.57 0.368 0 Mean 58.40.3 33 58.5 0.1 0 0 0 0 −0.307

TABLE 3 Group 2a patients. In this group, patients received lower doseby more than 10% than the calculated R × RSI. Adjustment of thesepatients dose could be done within standard of care range (50-70 Gy).Increase number Mean Mean treatment Mean Left Right Mean weeks ActualEsophageal Lung Lung Heart (rounded vs Increase Increase IncreaseIncrease up to Patient Actual R × RSI @ @ @ @ whole ID dose RSI GARD R ×RSI Dose Δ R × RSI R × RSI R × RSI R × RSI fraction) 16 45 0.272 29.26550.744 5.744 1.446 0.725 0.631 0.407 1 17 50 0.306 29.597 55.749 5.7491.448 0.726 0.632 0.408 1.2 18 50.4 0.315 29.112 57.131 6.731 1.695 0.850.74 0.477 0.2 19 46 0.318 26.33 57.654 11.654 2.934 1.472 1.281 0.8261.2 20 50 0.323 28.26 58.387 8.387 2.112 1.059 0.922 0.595 2 21 43.20.324 24.371 58.496 15.296 3.852 1.932 1.681 1.084 1.2 22 54 0.32830.107 59.189 5.189 1.307 0.655 0.57 0.368 0 23 54 0.334 29.577 60.2496.249 1.573 0.789 0.687 0.443 0.2 24 45 0.345 23.965 61.965 16.965 4.2722.143 1.864 1.203 1.2 25 54 0.345 28.757 61.967 7.967 2.006 1.006 0.8760.565 0.2 26 54 0.346 28.638 62.225 8.225 2.071 1.039 0.904 0.583 1.4 2754 0.353 28.152 63.3 9.3 2.342 1.175 1.022 0.659 0.4 28 50 0.353 26.01463.428 13.428 3.381 1.696 1.476 0.952 1.4 29 50.4 0.361 25.669 64.79414.394 3.624 1.818 1.582 1.021 1 30 60 0.389 28.293 69.983 9.983 2.5141.261 1.097 0.708 1 Mean 50.667 0.334 27.74 60.351 9.684 2.438 1.2231.064 0.687 0.907

TABLE 4 Group 2b patients. Similar to group 2a patients, these patientsreceived lower doses than the R × RSI. However dose adjustments forthese patients are outside the standard of care and in many cases resultin plans that do not meet DVH guideline criteria at our institutionIncrease number Mean Mean treatment Mean Left Right Mean weeks ActualEsophageal Lung Lung Heart (rounded vs Increase Increase IncreaseIncrease up to Patient Actual R × RSI @ @ @ @ whole ID dose RSI GARD R ×RSI Dose Δ R × RSI R × RSI R × RSI R × RSI fraction) 31 61.2 0.40727.475 73.507 12.307 3.099 1.554 1.353 0.873 0.6 32 55.8 0.412 24.73174.458 18.658 4.698 2.357 2.051 1.323 1.4 33 60 0.415 26.36 75.11515.115 3.806 1.909 1.661 1.072 1.6 34 60 0.453 23.765 83.315 23.3155.871 2.945 2.562 1.653 2.4 35 45 0.455 17.702 83.891 38.891 9.793 4.9124.274 2.757 3.4 36 64.8 0.467 24.697 86.587 21.787 5.486 2.752 2.3941.545 1.6 37 54 0.467 20.546 86.732 32.732 8.242 4.134 3.597 2.321 2.838 50.4 0.475 18.77 88.61 38.21 9.621 4.826 4.199 2.709 3.4 39 50 0.47518.601 88.704 38.704 9.746 4.888 4.254 2.744 4 40 55.8 0.475 20.74788.753 32.953 8.298 4.162 3.622 2.336 2.8 41 50 0.483 18.189 90.71440.714 10.252 5.142 4.475 2.887 4.2 42 50.4 0.496 17.648 94.242 43.84211.039 5.537 4.818 3.108 4 43 45 0.498 15.685 94.677 49.677 12.509 6.2745.46 3.522 4 44 54 0.499 18.764 94.971 40.971 10.316 5.175 4.503 2.9053.6 45 60 0.503 20.638 95.939 35.939 9.049 4.539 3.95 2.548 3.6 Mean54.427 0.465 20.954 86.681 32.254 8.122 4.074 3.545 2.287 2.893

TABLE 5 Group 3 patients. In this group, patients receive a higher doseby more than 10% than the calculated R × RSI. Adjustments to dose onthese patients sometimes were set to a minimum dose of 50 Gy. DecreaseActual number vs Mean Mean treatment R × RSI Actual Mean Left Right Meanweeks R × RSI min vs Esophageal Lung Lung Heart (rounded minimum 50 Gy R× RSI Decrease Decrease Decrease Decrease up to Patient Actual set toDose Dose @ @ @ @ whole ID dose RSI GARD 50 Gy R × RSI Δ Δ R × RSI R ×RSI R × RSI R × RSI fraction) 1 59.4 0.015 124.775 50 15.71 9.4 43.692.367 1.187 1.033 0.666 1.6 2 59.4 0.092 70.758 50 27.703 9.4 31.6972.367 1.187 1.033 0.666 1.6 3 60 0.118 64.117 50 30.881 10 29.119 2.5181.263 1.099 0.709 1 4 70 0.166 62.947 50 36.698 20 33.302 5.036 2.5262.198 1.418 2 5 66 0.177 57.198 50 38.078 16 27.922 4.029 2.021 1.7581.134 1.6 6 50 0.16 45.875 50 35.967 0 14.033 0 0 0 0 1.6 7 50 0.16844.588 50 37.006 0 12.994 0 0 0 0 1 8 54 0.198 43.788 50 40.696 4 13.3041.007 0.505 0.44 0.284 1 9 60 0.238 43.028 50 46.016 10 13.984 2.5181.263 1.099 0.709 1 10 60 0.239 42.907 50 46.146 10 13.854 2.518 1.2631.099 0.709 1 11 60 0.248 41.802 50 47.366 10 12.634 2.518 1.263 1.0990.709 2 12 70 0.304 41.671 55.435 55.435 14.565 14.565 3.668 1.84 1.6011.033 1 13 60 0.254 41.159 50 48.106 10 11.894 2.518 1.263 1.099 0.709 214 70 0.323 39.564 58.387 58.387 11.613 11.613 2.924 1.467 1.276 0.823 115 54 0.239 38.621 50 46.141 4 7.859 1.007 0.505 0.44 0.284 1 Mean60.187 0.196 53.52 50.921 40.689 9.265 19.498 2.333 1.17 1.018 0.6571.36

Finally, in Group 3 patients (15/60), the radiotherapy dose prescribedwas higher than the estimated RxRSI with a mean dose difference of 19.5Gy Table 5), suggesting an opportunity for iso-curative personalizeddose de-escalation. However, since some of the proposed RxRSIprescription doses fall below the clinically acceptable range (below 50Gy), a dose of 50 Gy was re-assigned to all patients with an RxRSI<50Gy. With this adjustment the mean dose difference was 9.27 Gy. Insummary, only a quarter (15/60) of the patients received the RxRSIthrough the empiric radiotherapy dose approach that we use every day inthe clinic. A personalized approach could have delivered thebiologically-optimized RxRSI to an additional 30 patients in the cohortwithout the need to dose-escalate beyond acceptable, safe doses withinthe current standard of care for this clinical situation. The remaining15 patients, who could not be optimized with dose escalation within SOC,could be excellent candidates for clinical trials. In conclusion, thedose prescribed and the RxRSI did not match by a clinically significantdegree for 75% of the cohort patients suggesting a large opportunity foroptimization both by personalized dose escalation and de-escalation.

Personalized RT Dose Prescription is Feasible without Impacting Risk ofNormal Tissue Toxicity

Any cytotoxic therapy, including radiation, can act as a double edgedsword. Not only does its judicious application result in beneficialoncologic effects, but it also results in normal tissue toxicity.Therefore, any under or over-dosing results in either sub-optimaloncologic effect or greater than needed normal tissue complications,which can also affect quality of life and survival. To quantify this,the impact of personalized dose adjustment on normal tissue wascalculated for the patients in the clinical cohort using the linearmodel generated from the genomic radiation plans (FIG. 5 ).

In Group 3 patients (patients who received higher doses than RxRSI),adjustment to the RxRSI (set to a minimum dose of 50 Gy) would haveresulted in an overall mean dose decrease to the esophagus, right andleft lung and heart (Tables 3, 4). In Group 2a patients (patients whoreceived lower doses than RxRSI), adjustment to the RxRSI would haveresulted in a mean increase in dose to normal tissue. The estimatedincrease in mean esophageal, right lung, left lung and heart dose is2.43 Gy, 1.22 Gy, 1.06 Gy and 0.68 Gy, respectively. The mean increasein normal tissue dose for group 2a patients (RxRSI>Dose received) isvery similar to mean decreases experienced by group 3 patients(RxRSI<Dose received). Thus, since Group 1 and 2b patients are notadjusted (group 1 RxRSI=Dose received and group 2b RxRSI is above SOCrange), the overall risk profile for normal tissue complications for thewhole population is not expected to be affected by the dose adjustmentsproposed by RxRSI.

Finally, the impact of dose adjustments on the risk of normal tissuecomplications was estimated. As shown in Table 6, patients who receiveda higher dose than their RxRSI (group 3) were potentially exposed toadditional risks including a major coronary event (5.1%), pneumonitis(0.6%) and esophagitis (0.2%). In Group 2a patients, where RxRSI waswithin standard of care but higher than the empirical dose received,dose adjustment would have increased the risk of these toxicities forthese patients by a similar magnitude.

TABLE 6 Estimating the impact of personalized dose adjustments (R × RSI)on normal tissue risk Risk of Left right major esophagus lung radiationlung Δ radiation heart coronary Δ dose esophagitis Δ dose pneumonitisdose pneumonitis Δ dose event Group −2.438 −0.2% −1.223 −0.7% −1.064−0.6% −0.687 −5.1% 2A Group −8.122 −1.5% −4.074 −2.9% −3.545 −2.2%−2.287 −16.9% 2B Group 3 2.333 0.2% 1.17 0.7% 1.018 0.5% 0.657 4.9%

A Personalized Radiation Dose Model Predicts the Failure of UnselectedEmpiric RT Dose Escalation in Lung Cancer

To estimate the clinical potential for personalized prescription RTdose, a model was built to quantify the impact of optimal RT dose onlocal control and toxicity in the lung cancer clinical cohort (precisionRxRSI model). GARD was utilized as the parameter to define biologicallyoptimal dose (RxRSI), where clinical outcome (local control) isoptimized when the GARD threshold (GARD=33) is achieved. In addition,the model incorporates a relative penalization scheme based on the addedtoxicity to which patients are potentially exposed when their RxRSI isexceeded. The model output is pLC (penalized local control), whichincludes local recurrence and events related to RT-related toxicity, butdoes not account for death due to other causes or disease progression.This model is a radiation outcome specific model. As shown in FIG. 2A,the precision RxRSI model reproduced the observed local control in theMoffitt lung cancer cohort when the cohort is dichotomized by GARD andthe average local control for the cohort when treated empirically to adose from 50-70 Gy. Patients that are biologically optimized byachieving a GARD of 33, maximize their outcome at a 5 year pLC thatapproximates 80%.

To validate the precision RxRSI model, the model was tested as towhether it would predict the confounding results observed in RTOG 0617,a recent Phase 3 clinical trial that compared 60 Gy to 74 Gy andcarboplatin and taxol vs. carbo, taxol and cetuximab in patients withNSCLC. As shown in FIG. 2B, the precision RxRSI model predicts thatuniform dose escalation to 74 Gy to unselected patients would result inno radiation-associated overall gains when compared to 60 Gy, consistentwith the results observed in the actual clinical trial. To furtherunderstand the biological underpinnings to explain this result, theproportion of patients that were expected to derive a benefit from doseescalation to 74 Gy were determined. As shown in FIG. 2C, 41.3% of thepatients achieved GARD 33 at 60 Gy. An additional 16.2% reached the GARDtarget at 74 Gy. However, the model predicted that still about 42.5% ofthe patients may need higher doses (>74 Gy). Thus, in an unselectedpopulation, uniform dose escalation to 74 Gy benefits only a minority ofpatients and exposes the majority of patients to additional toxicity,obfuscating any radiation-associated clinical gains. Finally, as shownin FIG. 2D, the precision RxRSI model correctly predicts the 1-year and2-year local control observed in RTOG 0617.

Optimizing RT Dose Using the RxRSI-Precision Model Shows SignificantPotential to Improve Radiation-Associated Clinical Outcome in LungCancer

To quantify the clinical opportunity provided by personalized RTprescription dose, in-silico clinical trials utilizing the precisionRxRSI model were performed. Thus, it was analyzed whether assigning 60or 74 Gy to patients based on their RxRSI would improve the outcome forthe whole cohort. The hypothesis is that only a subset of patientsderives benefit from dose escalation to 74 Gy. Therefore, in thisstrategy all patients were assigned 60 Gy, except the patients with anRxRSI between 62-74 Gy. As shown in FIG. 3A, this strategy wouldsignificantly improve the predicted radiation-associated outcome for thecohort (HR1.16, p<0.05). When the cohort of patients with RxRSI 62-74were analyzed independently, a large difference in radiation-associatedoutcome was predicted for the genomically-guided dose escalation (HR,4.15). In contrast, the rest of the patients in the cohort derived nobenefit from escalating the dose to 74 Gy (FIG. 3B).

Discussion

In this disclosure, a clinically-feasible system to personalize RTprescription based on biological parameters and for improving clinicaloutcomes inherent in personalized RT for patients with NSCLC arepresented. Personalized RT prescription is based on three parameters: 1.RSI which defines the patient's individual tumor radiosensitivity, 2.GARD, which defines the individualized clinical effect of a given doseof RT in a given patient with a distinct RSI and 3. RxRSI, orbiologically-optimal RT prescription dose, which we define as theprescription dose required to achieve a GARD target value associatedwith improved clinical outcome. Personalized RT prescription provides analternative to the empiric-based one-size fits all approach that iscurrently standard in the field.

The personalized genomics-based RT prescription system demonstrates thatprescribing uniform, empiric-based RT dose is biologically imprecise,with 75% of patients receiving non-optimal doses of RT. Conversely, itis shown that the personalized, RxRSI-based prescription approach candeliver optimal doses to up to 75% of the patients in the clinicalcohort even when a dose range is restricted within the standard of care.And this can be achieved without an overall increase in expected normaltissue toxicity for the whole cohort. To quantify the clinical potentialof personalized RT prescription and to improve outcomes in lung cancer,a novel methodology that combines the biological optimization of tumordose based on RSI/GARD and the individualized impact on normal tissuetoxicity of the personalized dose adjustment was developed. Theprecision RxRSI model assumes an ideal biological dose to maximize tumorcontrol and estimates outcome based on whether the RxRSI is achieved. Inaddition, it incorporates a penalization scheme based on the addedtoxicity to which patients are potentially exposed when their RxRSI isexceeded.

To validate the precision RxRSI model, the model was tested usingpublished data from RTOG-0617, a Phase 3 randomized trial in lung cancerthat assessed whether a uniform 14 Gy dose escalation would result inclinical gains in lung cancer. The precision RxRSI model correctlypredicts both qualitatively and quantitatively the trial outcome: thatuniform, empiric dose escalation to 74 Gy does not result in anyradiation-associated clinical gains, and is secondary to the potentialgains in tumor control being outweighed by the number of patientsexposed to additional toxicity. However, a personalized strategy todeliver 74 Gy only to the patient subset most likely to benefit (RxRSI62-74 Gy), would have improved the radiation-associated outcome for thewhole cohort by 6.3%. Thus, it is proposed that the delivery ofbiologically inaccurate RT doses results in a significant detriment ofclinical outcome for lung cancer patients treated with RT.

While the classic LQ model predicts that every individual in apopulation has the same opportunity to benefit from uniform doseescalation, the precision RxRSI model predicts that only a minority ofpatients (16.2% in this analysis) have the opportunity to benefit fromdose escalation to 74 Gy. This opportunity to benefit is outweighed bythe potential increase in toxicity to the rest of the patients.Inspecting the distribution of RSI in the two cohorts for lung canceralso illustrates an interesting point. Dose escalation from 45-60 Gyresults in capturing the major share of the patients in the first peakof the distribution. However, escalation from 60-74 Gy only captures thetail of the first mode, and does not affect the second peak. Thisexplains how uniform dose escalation to 60 Gy shows benefit to theentire population, as the benefit outweighs the harm. In addition, theprecision RxRSI model postulates that 42% of the patients are stillundertreated at 74 Gy, which is consistent with the local failure ratereported in 0617. It is postulated that the distributions measured hereare conserved, and further analysis of them in different disease sitescould provide insight into opportunities for personalized doseescalation and de-escalation. On the strength of this analysis, it issubmitted that our lack of understanding of biological heterogeneity,and how to treat it, explains the failure of biologically naïve uniformdose escalation.

The system to personalize RT prescription disclosed herein has a numberof advantages over the current empiric approach. First, it accounts forbiological heterogeneity that is specific to RT, updating the naiveassumption of homogeneous biology across patients, which is inherent inthe empiric approach. Second, since it uses biological information toformulate an optimized and personalized RT prescription dose, itrequires that genomic data be collected for every patient. This providesthe framework to identify novel biology that impacts RT benefit. Thusthe precision RxRSI model is only the first step towards a moreefficient and optimal approach to RT prescription. In contrast, multiplePhase 3 clinical trials have demonstrated that additional clinicalbenefit from the empiric approach is unlikely. Critically, this novelpersonalized system can be utilized within the standard of careframework for RT dose. Thus, clinicians can start using the precisionRxRSI model and their clinical judgement to decide a biology-based RTdose for their patients without venturing outside safe, and recommendedprescription doses.

While significant interest has been focused on the development of bettertherapeutic agents including targeted agents and immunotherapy, RTremains a fundamental curative treatment for the majority of patientswith cancer. It has been estimated that 40% of all cancer cures are dueto RT. In contrast, to date, no targeted agent or immunotherapy hasshown similar curative potential in solid tumors. Shifting to abiology-based system will provide a new direction for radiation oncologywith multiple opportunities to improve clinical outcome. And thatopportunity is not small. Approximately, 50% of all cancer patientsreceive RT which translates to about 850,000 patients in the US. Amoderate improvement in RT-based cures of 5% would represent anadditional 42,500 patients potentially being cured. According to theAmerican Cancer Society, this is approximately the same number ofpatients that die from breast cancer every year in the US.

In conclusion, radiation oncology has employed an empiric uniformapproach to prescribe RT that is based on models developed and publishedover 70 years ago. It is demonstrated that this one-size fits allapproach is biologically inaccurate for the majority of patients, andresults in significant detriment of clinical outcome for patientstreated with RT. A new paradigm is proposed, where the field updates itsassumptions by acknowledging the biologically heterogeneity of tumorsand moves towards the delivery of biological optimal doses of RT.

The invention claimed is:
 1. A computer software configured to integratewith a radiation therapy treatment planning system, the computersoftware being configured to: assign a radiation sensitivity index (RSI)of a subject's tumor based at least in part on expression levels of oneor more signature genes in the tumor; calculate a recommendedpersonalized radiation dosage (RxRSI) for the subject based at least inpart on a pre-determined genomic adjusted radiation dose (GARD) valueand the RSI; and provide, to the radiation therapy treatment planningsystem, the recommended RxRSI as a radiation therapy dose for aradiation plan, wherein the computer software is embodied on anon-transitory computer readable medium, and wherein the pre-determinedGARD value is about 33 for non-small cell lung cancer.
 2. The computersoftware of claim 1, further being configured to: calculate therecommended RxRSI based in part on normal tissue toxicity for atreatment plan using the recommended RxRSI.
 3. The computer software ofclaim 2, further being configured to: calculate the normal tissuetoxicity based at least in part on risks to a plurality of tissue sites.4. The computer software of claim 3, wherein the plurality of tissuesites comprises esophagus, lung, and heart.
 5. The computer software ofclaim 2, further being configured to: receive, from the radiationtherapy treatment planning system, a plurality of radiation plans eachusing the recommended RxRSI; calculate normal tissue toxicity for eachradiation plan of the plurality of radiation plans; penalize eachradiation plan of the plurality of radiation plans based on the normaltissue toxicity of the radiation treatment plan; and provide, to theradiation therapy treatment planning system, at least one recommendedradiation plan that is least penalized of the plurality of radiationplans.
 6. The computer software of claim 1, further being configured to:calculate the recommended RxRSI based in part on a predefined standardof care dose range.
 7. The computer software of claim 1, further beingconfigured to: calculate a proposed RxRSI based for the subject based atleast in part on the pre-determined GARD value and the RSI; compare theproposed RxRSI to a predefined standard of care dose range; assign therecommended RxRSI a value within the predefined standard of care doserange when the proposed RxRSI is within or below the predefined standardof care dose range; and recommend consideration of the subject forclinical trial if the proposed RxRSI is above the predefined standard ofcare dose range.
 8. The computer software of claim 1, further beingconfigured to: apply a linear regression model to the expression levelsof the one or more signature genes in the tumor; and assign the RSIbased at least in part on the linear regression model.
 9. The computersoftware of claim 1, wherein the pre-determined GARD value is based atleast in part on a plurality of GARD values for subjects in a cohort.10. A method of developing a personalized radiation treatment plan, themethod comprising: assigning a radiation sensitivity index (RSI) of asubject's tumor based at least in part on expression levels of one ormore signature genes in the tumor; calculating a recommendedpersonalized radiation dosage (RxRSI) for the subject based at least inpart on a pre-determined genomic adjusted radiation dose (GARD) valueand the RSI; and providing the recommended RxRSI as a radiation therapydose for a radiation plan, wherein the pre-determined GARD value isabout 33 for non-small cell lung cancer.
 11. The method of claim 10,further comprising: calculating the recommended RxRSI based in part onnormal tissue toxicity for a treatment plan using the recommended RxRSI.12. The method of claim 11, further comprising: calculating the normaltissue toxicity based at least in part on risks to a plurality of tissuesites.
 13. The method of claim 12, wherein the plurality of tissue sitescomprises esophagus, lung, and heart.
 14. The method of claim 11,further comprising: calculating a respective normal tissue toxicity foreach radiation plan of a plurality of radiation plans each utilizing therecommended RxRSI; penalizing each radiation plan of the plurality ofradiation plans based on the normal tissue toxicity of the radiationtreatment plan; and providing at least one recommended radiation planthat is least penalized of the plurality of radiation plans.
 15. Themethod of claim 10, further comprising: determining whether therecommended RxRSI is within a predefined standard of care dose range.16. The method of claim 10, further comprising: calculating a proposedRxRSI based for the subject based at least in part on the pre-determinedGARD value and the RSI; comparing the proposed RxRSI to a predefinedstandard of care dose range; assigning the recommended RxRSI a valuewithin the predefined standard of care dose range when the proposedRxRSI is within or below the predefined standard of care dose range; andrecommending consideration of the subject for clinical trial if theproposed RxRSI is above the predefined standard of care dose range. 17.The method of claim 10, further comprising: applying a linear regressionmodel to the expression levels of the one or more signature genes in thetumor; and assigning the RSI based at least in part on the linearregression model.
 18. The method of claim 10, wherein the pre-determinedGARD value is based at least in part on a plurality of GARD values forsubjects in a cohort.